Prodrugs of secondary amine compounds

ABSTRACT

The present invention relates to compounds of Formula I:

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.13/714,830, filed on Dec. 14, 2012 (now U.S. Pat. No. 8,969,337) whichclaims the benefit of U.S. Provisional Application No. 61/576,244, filedon Dec. 15, 2011.

The entire teachings of the above applications are incorporated hereinby reference.

BACKGROUND OF THE INVENTION (i) Field of the Invention

The present invention relates to prodrugs of secondary amine compounds.

(ii) Background of the Invention

Drug delivery systems are often critical for the safe effectiveadministration of a biologically active agent. Perhaps the importance ofthese systems is best realized when patient compliance and consistentdosing are taken into consideration. For instance, reducing the dosingrequirement for a drug from four-times-a-day to a single dose per daywould have significant value in terms of ensuring patient compliance andoptimizing therapy.

Optimization of a drug's bioavailability has many potential benefits.For patient convenience and enhanced compliance it is generallyrecognized that less frequent dosing is desirable. By extending theperiod through which the drug is released, a longer duration of actionper dose is expected. This will then lead to an overall improvement ofdosing parameters such as taking a drug once a day where it haspreviously required four times a day dosing or once a week or even lessfrequently when daily dosing was previously required. Many drugs arepresently given at a once a day dosing frequency. Yet, not all of thesedrugs have pharmacokinetic properties that are suitable for dosingintervals of exactly twenty-four hours. Extending the period throughwhich these drugs are released would also be beneficial.

One of the fundamental considerations in drug therapy involves therelationship between blood levels and therapeutic activity. For mostdrugs, it is of primary importance that serum levels remain between aminimally effective concentration and a potentially toxic level. Inpharmacokinetic terms, the peaks and troughs of a drug's blood levelsideally fit well within the therapeutic window of serum concentrations.For certain therapeutic agents, this window is so narrow that dosageformulation becomes critical.

In an attempt to address the need for improved bioavailability, severaldrug release modulation technologies have been developed. Entericcoatings have been used as a protector of pharmaceuticals in the stomachand microencapsulating active agents using protenoid microspheres,liposomes or polysaccharides has been effective in abating enzymedegradation of the active agent. Enzyme inhibiting adjuvants have alsobeen used to prevent enzymatic degradation.

A wide range of pharmaceutical formulations provide sustained releasethrough microencapsulation of the active agent in amides of dicarboxylicacids, modified amino acids or thermally condensed amino acids. Slowrelease rendering additives can also be intermixed with a large array ofactive agents in tablet formulations.

While microencapsulation and enteric coating technologies impartenhanced stability and time-release properties to active agentsubstances these technologies suffer from several shortcomings.Incorporation of the active agent is often dependent on diffusion intothe microencapsulating matrix, which may not be quantitative and maycomplicate dosage reproducibility. In addition, encapsulated drugs relyon diffusion out of the matrix or degradation of the matrix, or both,which is highly dependent on the chemical properties and watersolubility of the active agent. Conversely, water-soluble microspheresswell by an infinite degree and, unfortunately, may release the activeagent in bursts with limited active agent available for sustainedrelease. Furthermore, in some technologies, control of the degradationprocess required for active agent release is unreliable. For example, anenterically coated active agent depends on pH to release the activeagent and, due to variability in pH and residence time, it is difficultto control the rate of release.

Several implantable drug delivery systems have utilized polypeptideattachment to drugs. Additionally, other large polymeric carriersincorporating drugs into their matrices are used as implants for thegradual release of drug. Yet another technology combines the advantagesof covalent drug attachment with liposome formation where the activeingredient is attached to highly ordered lipid films.

Thus, there is a need for an active agent delivery system that poses areduced potential risk to the patient, is able to deliver certain activeagents that have been heretofore not formulated (or are difficult toformulate in a sustained release formulation) for release over asustained period of time, and which is convenient for patient dosing.

There is a generally recognized need for sustained delivery of drugsthat can reduce the dosing requirement and allows for controlled andsustained release of the parent drug, and also avoids irregularities ofrelease and cumbersome formulations encountered with typical dissolutioncontrolled sustained release methods.

SUMMARY OF THE INVENTION

The present invention provides an alternative approach to prodrugs forsecondary amine and related compounds which results in reduced risks tothe patient. The invention also extends the period during which asecondary amine parent drug, or related compound, is released andabsorbed after administration to the patient and provides a longerduration of action per dose than is currently expected. In oneembodiment, the compounds suitable for use in the methods of theinvention are labile prodrugs of secondary amine parent drugs that arederivatized through carbamate-linked prodrug moieties that reduce thesolubility and polarity of the prodrug compound as compared to theparent drug. The carbamate linked esters are expected to get cleaved byesterases in vivo, releasing the chemically unstable intermediate whichthen releases the aldehyde linker and carbon dioxide.

In one embodiment, the invention provides compounds represented byFormula I:

wherein:R₁ is —C(O)OC(R₄)(R₅)—OC(O)(G₁₂)_(m)R₆;

-   -   wherein each R₄ and R₅ is independently selected from hydrogen,        C₁-C₃ alkyl, aryl or substituted aryl; preferably, hydrogen or        methyl;    -   G₁₂ is selected from absent, NH, CH₂, —S— or —O—;    -   m is 0 or 1;    -   R₆ is selected from C₁₃-C₂₆-alkyl, substituted C₁₃-C₂₆-alkyl,        C₁₃-C₂₆-alkenyl, substituted C₁₃-C₂₆-alkenyl, C₁₃-C₂₆-alkynyl,        substituted C₁₃-C₂₆-alkynyl, C₁₃-C₂₆-cycloalkyl, and substituted        C₁₃-C₂₆-cycloalkyl, aryl-C₁₃-C₂₆-alkyl, substituted        aryl-C₁₃-C₂₆-alkyl, C₁-C₁₀-aryl, substituted C₁-C₁₀-aryl,        heteroaryl-C₁₃-C₂₆-alkyl, substituted heteroaryl-C₁₃-C₂₆-alkyl;        optionally substituted C₁₃-C₂₆-alkylaryl, optionally substituted        C₁₃-C₂₆-alkenylaryl and optionally substituted        C₁₃-C₂₆-alkynylaryl;        R₂ and R₃, together with the nitrogen atom to which they are        attached, form a secondary amine-containing parent drug, or a        substituted secondary amine-containing parent drug.

In a preferred embodiment, the invention relates to a prodrug of FormulaI wherein upon administration to the patient, release of the parent drugfrom the prodrug is sustained release.

In another embodiment, the invention relates to pharmaceuticalcompositions comprising a compound of Formula I, a pharmaceuticallyacceptable carrier, and methods of using a compound of Formula I intherapy.

In a further embodiment, the prodrug compounds of the invention areformulated with a biocompatible sustained release delivery system fordelivery of the prodrug wherein the system is preferably capable ofminimizing accelerated hydrolytic cleavage of the prodrug by minimizingexposure of the prodrug to water. Preferred delivery systems includebiocompatible polymeric matrix delivery systems capable of minimizingthe diffusion of water into the matrix having the prodrug dispersedtherein.

In another embodiment, the invention provides a method of sustaineddelivery of a secondary amine-containing parent drug comprisingadministering to a subject an effective amount of a prodrug compoundproduced by substituting a labile, hydrophobic carbamate-linked prodrugmoiety (represented by —R₁) on the secondary amine nitrogen atom of theparent drug. Preferably the prodrug compound has decreased solubilityunder physiological conditions and sustained activity upon dosingcompared to the parent drug compound.

In one embodiment, the secondary amine-containing parent drug isrepresented by Formula II:

wherein R₂ and R₃ are as previously defined. In this embodiment theprodrug is represented by Formula I:

wherein R₁, R₂ and R₃ are as previously defined.

The invention also provides a method of administering a secondaryamine-containing parent drug comprising administering to a subject aneffective amount of a prodrug compound (Formula I) produced bysubstituting a labile, hydrophobic carbamate-linked prodrug moiety (—R₁)on the secondary amine nitrogen atom. The method substantiallyeliminates undesirable side effects seen upon administration of theparent drug itself by lowering the maximum plasma concentration of theparent drug while maintaining sustained therapeutic levels. In certainembodiments, the side effect of the parent drug is sedation. In apreferred embodiment, the prodrug compound is a compound of Formula Iand the parent drug is a compound of Formula II.

In another embodiment, the invention provides a method of producing aprodrug of a parent secondary amine-containing drug compound, whereinthe prodrug has decreased solubility under physiological conditions andsustained activity upon dosing compared to the parent drug compound. Themethod comprises modifying the parent drug by substituting a labile,hydrophobic prodrug moiety on the secondary amine nitrogen atom.Preferably, the parent drug compound is represented by Formula II, thelabile moiety is represented by R₁, where R₁ is as defined above, andthe prodrug is represented by Formula I.

The invention also provides pharmaceutical compositions comprising acompound of Formula I and methods of using a compound of Formula I intherapy.

FIGURES

FIG. 1: Mean plasma olanzapine concentration after intramuscularinjection of Compound-56, 111, and 112 to rats.

FIG. 2: Expanded view of mean plasma olanzapine concentration afterintramuscular injection of Compound-56, 111, and 112 to rats.

FIG. 3: Plasma concentrations of olanzapine and Compound-112 afterintramuscular administration of Compound-112.

FIG. 4: Plasma concentrations of olanzapine and Compound-111 afterintramuscular administration of Compound-111.

DETAILED DESCRIPTION OF THE INVENTION

The prodrug compounds of the present invention having the generalstructure of Formula I provide sustained or extended release to theparent drug, where the parent drug is produced by the enzymatic orhydrolytic cleavage of the labile R₁ group:

wherein:R₁ is —C(O)OC(R₄)(R₅)—OC(O)(G₁₂)_(m)R₆;

-   -   wherein each R₄ and R₅ is independently selected from hydrogen,        C₁-C₃ alkyl, aryl or substituted aryl; preferably, hydrogen or        methyl;    -   G₁₂ is selected from absent, NH, CH₂, —S— or —O—;    -   m is 0 or 1;    -   R₆ is selected from C₁₃-C₂₆-alkyl, substituted C₁₃-C₂₆-alkyl,        C₁₃-C₂₆-alkenyl, substituted C₁₃-C₂₆-alkenyl, C₁₃-C₂₆-alkynyl,        substituted C₁₃-C₂₆-alkynyl, C₁₃-C₂₆-cycloalkyl, and substituted        C₁₃-C₂₆-cycloalkyl, aryl-C₁₃-C₂₆-alkyl, substituted        aryl-C₁₃-C₂₆-alkyl, C₁-C₁₀-aryl, substituted C₁-C₁₀-aryl,        heteroaryl-C₁₃-C₂₆-alkyl, substituted heteroaryl-C₁₃-C₂₆-alkyl;        optionally substituted C₁₃-C₂₆-alkylaryl, optionally substituted        C₁₃-C₂₆-alkenylaryl and optionally substituted        C₁₃-C₂₆-alkynylaryl;        R₂ and R₃, together with the nitrogen atom to which they are        attached, form a secondary amine-containing parent drug or a        substituted secondary amine-containing parent drug.

In a preferred embodiment, the invention relates to a prodrug of FormulaI wherein upon administration to the patient, release of the parent drugfrom the prodrug is sustained release.

In one embodiment, the secondary amine-containing parent drug isrepresented by Formula II:

wherein R₂ and R₃ are as previously defined. In this embodiment theprodrug is represented by Formula I:

wherein R₁, R₂ and R₃ are as previously defined.

In one embodiment, R₆ is an optionally substituted C₁₃-C₂₆-aliphatic,C₁₃-C₂₆-aromatic, or C₁₃-C₂₆-alkoxy (carbonate) group that reduces thesolubility of the prodrug under physiological conditions compared to theparent drug.

In one embodiment, both R₄ and R₅ are hydrogen. In another embodiment,R₅ is hydrogen and R₄ is methyl. In yet a third embodiment, both R₄ andR₅ are methyl.

In one embodiment, the invention provides compounds of Formula I inwhich R₁ is selected from —C(O)OCH(R₄)—OC(O)R₆, —C(O)OCH(R₄)—OC(O)OR₆,—C(O)OCH(R₄)—OC(O)N(R₆)R₇, and —C(O)OCH(R₄)—OC(O)NHR₆, where R₄, R₅, andR₆, are as previously defined; R₇ is selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, aliphatic and substitutedaliphatic.

In one embodiment, R₆ or R₇ is optionally substituted C₁₃-C₂₆-alkyl,C₁₃-C₂₆-alkenyl, or C₁₃-C₂₆-alkynyl. In a preferred embodiment, R₆ isoptionally substituted C₁₅-C₂₄-alkyl, C₁₅-C₂₄-alkenyl, orC₁₅-C₂₄-alkynyl. In a more preferred embodiment, R₆ or R₇ is optionallysubstituted C₁₇-C₂₂-alkyl, C₁₇-C₂₂-alkenyl, or C₁₇-C₂₂-alkynyl. In amore preferred embodiment, R₆ is optionally substituted C₁₉-alkyl,C₁₉-alkenyl, or C₁₉-alkynyl. In a more preferred embodiment, R₆ isoptionally substituted C₁₇-alkyl, C₁₇-alkenyl, or C₁₇-alkynyl.

In one embodiment, R₆ or R₇ is a C₁₃-C₂₆- or C₁₃-C₂₆-alkyl, -alkenyl or-alkynyl group, corresponding to one of formulas (i)-(v) below.

In these groups, r is an integer selected from 11 to 24, and s is aninteger selected from 11 to 24. Each oft and u is independently aninteger selected from 1 to 24, provided that the sum oft and u is from12 to 34. Each of v, w and x is independently an integer selected from 1to 24, provided that the sum of v, w and x is from 13 to 44. z is aninteger selected from 1 to 10 and y is an integer selected from 11 to24. Preferably, r is an integer selected from 15 to 17; s is an integerselected from 15 to 17; the sum oft and u is selected from 16 to 26; thesum of v, w and x is selected from 17 to 35; and the sum of y and z isselected from 16 to 23. R₆ can also be an alkenyl or alkynyl groupderived from one of the alkyl groups of formulas (i) to (v), byreplacement of one or more carbon-carbon single bonds with acarbon-carbon double bond or a carbon-carbon triple bond.

In another embodiment, R₆ or R₇ is an optionally substituted β-branchedC₁₃-C₂₆-alkyl, C₁₃-C₂₆-alkenyl or C₁₃-C₂₆-alkynyl, preferably optionallysubstituted β-branched C₁₇-C₂₂-alkyl, C₁₇-C₂₂-alkenyl orC₁₇-C₂₂-alkynyl. Suitable examples of β-branched alkyl groups include2-methyl-C₁₃-C₂₆-alkyl and 2,2-dimethyl-C₁₃-C₂₆-alkyl, including2-methylpropyl; 2,2-dimethylpropyl; 2-methylbutyl; 2,2-dimethylbutyl;2-methylpentyl; 2,2-dimethylpentyl; and 2-ethyl-2-methylbutyl.

The secondary amine-containing parent drug can be any secondaryamine-containing parent drug that induces a desired local or systemiceffect. Such parent drugs include broad classes of compounds. Severalexamples include: respiratory drugs, including antiasthmatic agents;analgesic agents; antidepressants; antianginal agents; antiarrhythmicagents; antihypertensive agents; antidiabetic agents; antihistamines;anti-infective agents such as antibiotics; antiinflammatory agents;antiparkinsonism drugs; antipsychotics; antipyretic agents; antiulceragents; attention deficit hyperactivity disorder (ADHD) drugs; centralnervous system stimulants; cough and cold preparations, includingdecongestants; and psychostimulants.

Examples of secondary-amine containing parent drugs from which prodrugsof the invention may be derived include: alprenolol, acebutolol,amidephrine, amineptine, amosulalol, amoxapine, amphetaminil, atenolol,atomoxetine, balofloxacin, bamethan, befunolol, benazepril, benfluorex,benzoctamine, betahistine, betaxolol, bevantolol, bifemelane,bisoprolol, brinzolamide, bufeniode, butethamine, camylofine, carazolol,carticaine, carvedilol, cephaeline, ciprofloxacin, clozapine,clobenzorex, clorprenaline, cyclopentamine, delapril, demexiptiline,denopamine, desipramine, desloratadine (clarinex), diclofenac,dimetofrine, dioxadrol, dobutamine, dopexamine, doripenem, dorzolamide,droprenilamine, duloxetine, eltoprazine, enalapril, enoxacin,epinephrine, ertapenem, esaprazole, esmolol, etoxadrol, fasudil,fendiline, fenethylline, fenfluramine, fenoldopam, fenoterol,fenproporex, flecainide, fluoxetine, formoterol, frovatriptan,gaboxadol, garenoxacin, gatifloxacin, grepafloxacin, hexoprenaline,imidapril, indalpine, indecainide, indeloxazine hydrochloride,isoxsuprine, ispronicline, labetalol, landiolol, lapatinib,levophacetoperane, lisinopril, lomefloxacin, lotrafiban, maprotiline,mecamylamine, mefloquine, mepindolol, meropenem, metapramine,metaproterenol, methoxyphenamine, dtmp (dextrorotary methylphenidate),methylphenidate, metipranolol, metoprolol, mitoxantrone, mivazerol,moexipril, moprolol, moxifloxacin, nebivolol, nifenalol, nipradilol,norfloxacin, nortriptyline, nylidrin, olanzapine, oxamniquine,oxprenolol, oxyfedrine, paroxetine, perhexiline, phenmetrazine,phenylephrine, phenylpropylmethylamine, pholedrine, picilorex,pimefylline, pindolol, pipemidic acid, piridocaine, practolol,pradofloxacin, pramipexole, pramiverin, prenalterol, prenylamine,prilocaine, procaterol, pronethalol, propafenone, propranolol,propylhexedrine, protokylol, protriptyline, pseudoephedrine, reboxetine,rasagiline, (r)—rasagiline, repinotan, reproterol, rimiterol, ritodrine,safinamide, salbutamol/albuterol, salmeterol, sarizotan, sertraline,silodosin, sotalol, soterenol, sparfloxacin, spirapril, sulfinalol,synephrine, tamsulosin, tebanicline, tianeptine, tirofiban, tretoquinol,trimetazidine, troxipide, varenicline (champix), vildagliptin,viloxazine, viquidil and xamoterol.

Preferred secondary amine-containing parent drugs from which prodrugs ofthe invention are derived include atenolol, atomoxetine, clozapine,desipramine, desloratadine (clarinex), diclofenac, doripenem,duloxetine, enalapril, ertapenem, fluoxetine, metoprolol, mecamylamine,meropenem, methylphenidate, dtmp (dextrorotary methylphenidate),olanzapine, paroxetine, pramipexole, rasagiline, (r)—rasagiline,salbutamol/albuterol, tamsulosin, varenicline (chantix), andvildagliptin. In a more preferred embodiment, the secondaryamine-containing parent drug is selected from clozapine, duloxetine,mecamylamine, pramipexole, rasagiline, (r)—rasagiline, and olanzapine.

In a preferred embodiment, a compound of the invention providessustained delivery of the parent drug over hours, days, weeks or monthswhen administered parenterally to a subject. For example, the compoundscan provide sustained delivery of the parent drug for up to 7, 15, 30,60, 75 or 90 days or longer. Without being bound by theory, it isbelieved that the compounds of the invention form an insoluble depotupon parenteral administration, for example subcutaneous, intramuscularor intraperitoneal injection.

The present invention is intended to encompass any parent drug compoundor any substituted parent drug compound which contains a secondary aminegroup and which is biologically active and can be derivatized accordingto the present invention to afford the corresponding compounds offormula I. While the secondary amine-containing parent drugs from whichthe prodrugs of the invention may be derived are numerous, many of thechemical structures of the prodrugs of the invention can becharacterized by certain general structure types. One type includesthose wherein the secondary amine nitrogen is part of a cyclic(including bicyclic or tricyclic) aliphatic group such as piperidine,piperazine, morpholine, pyrrolidine, azapine, and diazapine. Anothertype includes those wherein the secondary amine nitrogen is a linearamine within an aliphatic chain, or as a diaryl amine or an aromaticamine. Examples of secondary amine-containing parent drugs, and thefunctional secondary amine group which provides the site of attachmentof the carbamate-linked prodrug moiety, are provided in the sectionbelow. Unless otherwise stated, the structural formula of a compoundherein is intend to represent all enantiomers, racemates anddiastereomers of that compound.

Prodrugs of Atenolol

Atenolol is a known beta adrenergic blocker that is used in thetreatment of hypertension, angina, and arrhythmia. Its chemical name is2-(4-{2-hydroxy-3-[(propan-2-yl)amino]propoxy}phenyl)acetamide. In oneembodiment, the invention relates to a prodrug of atenolol having thefollowing structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Atomoxetine

Atomoxetine is used in the treatment of attention-deficit hyperactivitydisorder (ADHD). Its chemical name is(−)-N-methyl-γ-(2-methylphenoxy)benzenepropanamine. In one embodiment,the invention relates to a prodrug of atomoxetine having the followingstructure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of DesipramineDesipramine is used in the treatment of depression. Its chemical name is3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine. Inone embodiment, the invention relates to a prodrug of desipramine havingthe following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Diclofenac

Diclofenac is a non-steroidal anti-inflammatory agent (NSAID withantipyretic and analgesic actions. Its chemical name is2-{2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid. In one embodiment,the invention relates to a prodrug of diclofenac having the followingstructure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Duloxetine

Duloxetine is a known selective serotonin-norepinephrine reuptakeinhibitor (selective SNRI) that is used in the treatment of depressionand anxiety. Its chemical name ismethyl[(3S)-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propyl]amine. In oneembodiment, the invention relates to a prodrug of duloxetine having thefollowing structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Enalapril

Enalapril is a known angiotensin-converting enzyme (ACE) inhibitor thatis used in the treatment of hypertension. Its chemical name is(2S)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]pyrrolidine-2-carboxylicacid. In one embodiment, the invention relates to a prodrug of enalaprilhaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Fluoxetine

Fluoxetine is a known highly specific serotonin uptake inhibitor that isused in the treatment of depression. Its chemical name ismethyl({3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl})amine. In oneembodiment, the invention relates to a prodrug of fluoxetine having thefollowing structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Metoprolol

Metoprolol is a known cardioselective β1-adrenergic blocking agent usedin the treatment of acute myocardial infarction (MI), heart failure,angina pectoris and mild to moderate hypertension. Its chemical name is{2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]propyl}(propan-2-yl)amine. Inone embodiment, the invention relates to a prodrug of metoprolol havingthe following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Mecamylamine

Mecamylamine is a known nicotinic antagonist used in the treatment ofsmoking addiction and depression. Its chemical name isN,2,3,3-tetramethylbicyclo[2.2.1]heptan-2-amine. In one embodiment, theinvention relates to a prodrug of mecamylamine having the followingstructure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Pramipexole

Pramipexole is a known non-ergoline dopamine agonist used in thetreatment of Parkinson's disease and restless legs syndrome (RLS). Itschemical name is(6R)-6-N-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine. In oneembodiment, the invention relates to a prodrug of pramipexole having thefollowing structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Rasagiline

Rasagiline is a known irreversible inhibitor of monoamine oxidase usedin the treatment of Parkinson's disease. Its chemical name is(1R)-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine. In one embodiment,the invention relates to a prodrug of rasagiline having the followingstructure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.(R)—Rasagiline

(R)—Rasagiline is a known irreversible inhibitor of monoamine oxidaseused in the treatment of Parkinson's disease. Its chemical name is(1R)-N-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-amine. In one embodiment,the invention relates to a prodrug of (R)—rasagiline having thefollowing structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Salbutamol

Salbutamol is a known short-acting, selective beta2-adrenergic receptoragonist used in the treatment of asthma and Chronic ObstructivePulmonary Disease (COPD). The chemical name of salbutamol is4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol. In oneembodiment, the invention relates to a prodrug of salbutamol having thefollowing structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Tamsulosin

Tamsulosin is a known selective antagonist of alpha-1A andalpha-1B-adrenoceptors that is used in the treatment of hypertrophy ofthe prostate. Its chemical name is5-[(2R)-2-{[2-(2-ethoxyphenoxyl)ethyl]amino}propyl]-2-methoxybenzene-1-sulfonamide.In one embodiment, the invention relates to a prodrug of tamsulosinhaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Vildagliptin

Vildagliptin is a known anti-hyperglycemic agent (anti-diabetic drug) ofthe dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs that is usedto inhibit the inactivation of glucagon-like peptide-1 (GLP-1) andglucose-dependent insulinotropic polypeptide (GIP) by DPP-4. Itschemical name is(2S)-1-{2-[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile.In one embodiment, the invention relates to a prodrug of vildagliptinhaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrug Chemistry Via Secondary Nitrogen of Azepine MoietyProdrugs of Varenicline

Varenicline is a known partial agonist of the alpha4/beta2 subtype ofthe nicotinic acetylcholine receptor that is used in the treatment ofsmoking addiction. Its chemical name is7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino (2,3-h)(3) benzazepine. Inone embodiment, the invention relates to a prodrug of varenicline havingthe following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrug Chemistry via Secondary Nitrogen of Diazepine MoietyClozapine

Clozapine is a known atypical antipsychotic agent that used in thetreatment of neurodisorders. Its chemical name is8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine. Inone embodiment, the invention relates to a prodrug of clozapine havingthe following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.

In one embodiment, the invention relates to a prodrug of clozapinehaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Olanzapine

Olanzapine is a known atypical antipsychotic that is used in thetreatment of schizophrenia and bipolar disorder as well as otherneurodisorders. Its chemical name is2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.In one embodiment, the invention relates to a prodrug of olanzapinehaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.

In one embodiment, the invention relates to a prodrug of olanzapinehaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrug Chemistry via Secondary Nitrogen of Piperidine MoietyDesloratadine

Desloratadine is a known H1-antagonist and is used as a non-sedatingantihistamine. Its chemical name is8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine.In one embodiment, the invention relates to a prodrug of desloratadinehaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Methylphenidate

Methylphenidate is a known psychostimulant that is used in the treatmentof attention deficit disorders and narcolepsy. Its chemical name ismethyl 2-phenyl-2-(piperidin-2-yl)acetate. In one embodiment, theinvention relates to a prodrug of methylphenidate having the followingstructure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Dexmethylphenidate

Dexmethylphenidate is the dextrorotary form of methylphenidate. It is anorepinephrine-dopamine reuptake inhibitor (NDRI) and a psychostimulant,and is used for the treatment of Attention Deficit HyperactivityDisorder (ADHD). Its chemical name is methyl(2R)-2-phenyl-2-[(2R)-piperidin-2-yl]acetate. In one embodiment, theinvention relates to a prodrug of dexmethylphenidate having thefollowing structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Paroxetine

Paroxetine is a known serotonin uptake inhibitor that is used in thetreatment of depression. Its chemical name is(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine.In one embodiment, the invention relates to a prodrug of peroxetinehaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrug Chemistry via Secondary Nitrogen of Pyrrolidine MoietyDoripenem

Doripenem is a known broad spectrum antibiotic that is used in thetreatment of bacterial infections. Its chemical name is(4R,5S,6S)-6-(1-hydroxyethyl)-4-methyl-7-oxo-3-[(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl]sulfanyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid. In one embodiment, the invention relates to a prodrug of doripenemhaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Ertapenem

Ertapenem is a known broad spectrum antibiotic that is used in thetreatment of bacterial infections. Its chemical name is(4R,5S,6S)-3-{[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]pyrrolidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid. In one embodiment, the invention relates to a prodrug of ertapenemhaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.Prodrugs of Meropenem

Meropenem is a known broad spectrum antibiotic that is used in thetreatment of bacterial infections. Its chemical name is(4R,5S,6S)-3-{[(2S,5S)-5-(dimethylcarbamoyl)pyrrolidin-2-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid. In one embodiment, the invention relates to a prodrug of meropenemhaving the following structure:

wherein R₁ is as defined above; preferably R₁ is selected from thestructures of Tables 1-3.

In preferred embodiments, R₁ in formula I is selected from Tables 1-3.

TABLE 1

TABLE 2

TABLE 3

wherein each j is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27; andeach k is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In a further embodiment, the prodrug compounds of the invention areformulated with a biocompatible sustained release delivery system fordelivery of the prodrug wherein the system is preferably capable ofminimizing accelerated hydrolytic cleavage of the prodrug by minimizingexposure of the prodrug to water. Preferred delivery systems includebiocompatible polymeric matrix delivery systems capable of minimizingthe diffusion of water into the matrix having the prodrug dispersedtherein.

In another embodiment, the invention provides a method of sustaineddelivery of a secondary amine-containing parent drug comprisingadministering to a subject an effective amount of a prodrug compoundproduced by substituting a labile, hydrophobic carbamate-linked prodrugmoiety (represented by —R₁) on the secondary amine nitrogen atom of theparent drug. Preferably the prodrug compound has decreased solubilityunder physiological conditions and sustained activity upon dosingcompared to the parent drug compound.

Sustained release drug formulations often contain higher amounts ofdrugs than immediate release formulations. Functionality and safety of asustained release formulation are based on a reliable and controlledrate of drug release from the formulation over an extended period oftime after administration. The drug release profile of a formulationoften depends on the chemical environment of the sustained releaseformulation, for example, on pH, ionic strength and presence of solventssuch as ethanol.

The relatively high amount of drug that is present in a sustainedrelease formulation can, in some instances, harm a patient if theformulation releases the drug at a rate that is faster than the intendedcontrolled release rate. If the formulation releases the drug at a ratethat is slower than the intended controlled release rate, thetherapeutic efficacy of the drug can be reduced.

In most cases, partial or total failure of a sustained releaseformulation results in a rapid release of the drug into the bloodstream.This rapid release is generally faster than the intended sustainedrelease of the drug from the formulation, and is sometimes referred toas “dose dumping.”

Dose dumping can create severe consequences for a patient, includingpermanent harm and even death. Examples of drugs that can be fatal ifthe therapeutically beneficial dose is exceeded, e.g., by dose dumping,include pain medications such as opioids, as well as other agents activein the central nervous system. In those situations where dose dumpingmay not be fatal, dose dumping may at least be responsible for the sideeffect of sedation or coma in the patient.

In a preferred embodiment, a compound of the invention providessustained delivery of the parent drug over hours, days, weeks or monthswhen administered, for example, orally or parenterally, to a subject.For example, the compounds can provide sustained delivery of the parentdrug for up to 7, 15, 30, 60, 75 or 90 days or longer. Without beingbound by theory, it is believed that the compounds of the invention forman insoluble depot upon parenteral administration, for examplesubcutaneous, intramuscular or intraperitoneal injection.

The term “labile” as used herein refers to the capacity of the prodrugof the invention to undergo enzymatic and/or chemical cleavage in vivothereby forming the parent drug. As used herein the term “prodrug” meansa compounds as disclosed herein which is a labile derivative compound ofa parent drug which when administered to a patient in vivo becomescleaved by chemical and/or enzymatic hydrolysis thereby forming theparent drug such that a sufficient amount of the compound intended to bedelivered to the patient is available for its intended therapeutic usein a sustained release manner.

The terms “sustained release”, “sustained delivery” and “extendedrelease” are used interchangeably herein to indicate that the prodrugsof the invention provide release of the parent drug by any mechanismincluding slow first-order kinetics of absorption or zero-order kineticsof absorption, such that the parent drug which is released from theprodrug provides a longer duration of action than the duration of actionof the parent drug when administered alone (i.e. not as a prodrug of theinvention). In accordance with the invention, “sustained release” of theprodrugs of the invention may include other pharmacokinetic indices suchas a lower maximum concentration (Cmax) of parent drug in the bloodand/or an extended period of time for the parent drug to reach maximumconcentration in the blood (Tmax) as compared to the Cmax and Tmax whenthe parent drug is administered alone. Sustained release may alsodecrease concentration fluctuations in the body, as indicated by plasmaconcentration-time profiles.

It is understood that any of the parent prodrugs of the invention may befurther substituted as that term is defined herein, so long as thesubstituted parent drug or parent prodrug, which when administered to apatient in vivo, becomes cleaved by chemical and/or enzymatic hydrolysisthereby releasing the parent drug moiety such that a sufficient amountof the compound intended to be delivered to the patient is available forits intended therapeutic use in a sustained release manner. A parentdrug or parent prodrug may be further substituted for any purposeincluding, but not limited to, stabilization of the parent duringsynthesis of the prodrug and stabilization of the prodrug foradministration to the patient.

In one embodiment, the present invention provides a method of treating aneurological or psychiatric disorder or disease in a patient in needthereof, by conjugating a labile moiety to a parent drug useful fortreating a neurological or psychiatric disorder or disease. The methodcomprises administering to the subject a therapeutically effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt thereof.

The term “neurological or psychiatric disorder”, as this term is usedherein, is a disease or disorder of the central nervous system that ismanifested in mood and/or behavioral abnormalities. Examples ofneurological or psychiatric disorders include, but are not limited to,disorders such as cerebral deficit subsequent to cardiac bypass surgeryand grafting, stroke, cerebral ischemia, spinal cord trauma, headtrauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage,dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, Parkinsonism, muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, cerebral deficits secondary to prolonged statusepilepticus, migraine (including migraine headache), urinaryincontinence, substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, social phobia, obsessive compulsive disorder, andpost-traumatic stress disorder (PTSD)), attention deficit disorder(ADD), attention deficit hyperactivity disorder (ADHD), mood disorders(including depression, mania, bipolar disorders), circadian rhythmdisorders (including jet lag and shift work), trigeminal neuralgia,hearing loss, tinnitus, macular degeneration of the eye, emesis, brainedema, pain (including acute and chronic pain states, severe pain,intractable pain, neuropathic pain, inflammatory pain, andpost-traumatic pain), tardive dyskinesia, sleep disorders (includingnarcolepsy), attention deficit/hyperactivity disorder, and conductdisorder.

In another embodiment, the present invention provides a method oftreating cardiac and cardiovascular disorders such as angina,arrhythmia, and hypertension, in a patient in need thereof. The methodcomprises administering to the subject a therapeutically effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt thereof.

The invention further relates to the treatment of fever, diabetes,allergy, asthma, infection, inflammation, and ulcers in a patient inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof.

The invention further relates to the treatment of sleep modulationcomprising administration of a compound of Formula I. Sleep modulationincludes decreasing the time to sleep onset, increasing the averagesleep bout length, and increasing the maximum sleep bout length.

The term “treatment” refers to any process, action, application,therapy, or the like, wherein a mammal, including a human being, issubject to medical aid with the object of improving the mammal'scondition, directly or indirectly.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;cyclodextrins such as alpha—(α), beta—(β) and gamma—(γ) cyclodextrins;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethylcellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In a preferredembodiment, administration is parenteral administration by injection.

The pharmaceutical compositions of this invention may contain anyconventional non-toxic pharmaceutically-acceptable carriers, adjuvantsor vehicles. In some cases, the pH of the formulation may be adjustedwith pharmaceutically acceptable acids, bases or buffers to enhance thestability of the formulated compound or its delivery form. The termparenteral as used herein includes subcutaneous, intracutaneous,intravenous, intramuscular, intraarticular, intraarterial,intrasynovial, intrasternal, intrathecal, intralesional and intracranialinjection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, acetamide, oils (in particular, cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.INTRALIPID® is an intravenous fat emulsion containing 10-30% soybeanoil, 1-10% egg yolk phospholipids, 1-10% glycerin and water. LIPOSYN® isalso an intravenous fat emlusion containing 2-15% safflower oil, 2-15%soybean oil, 0.5-5% egg phosphatides 1-10% glycerin and water. OMEGAVEN®is an emulsion for infusion containing about 5-25% fish oil, 0.5-10% eggphosphatides, 1-10% glycerin and water. Among the acceptable vehiclesand solvents that may be employed are water, Ringer's solution, U.S.P.and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are used inthe preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Additional sustained release in accordance with the invention may beaccomplished by the use of a liquid suspension of crystalline oramorphous material with poor water solubility. The rate of absorption ofthe drug then depends upon its rate of dissolution, which, in turn, maydepend upon crystal size and crystalline form. Alternatively, delayedabsorption of a parenterally administered drug form is accomplished bydissolving or suspending the drug in an oil vehicle. Injectable depotforms are made by forming microencapsule matrices of the drug inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of drug to polymer and the nature of the particular polymeremployed, the rate of drug release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping the drugin liposomes or microemulsions that are compatible with body tissues.

In one preferred embodiment, the formulation provides a sustainedrelease delivery system that is capable of minimizing the exposure ofthe prodrug to water. This can be accomplished by formulating theprodrug with a sustained release delivery system that is a polymericmatrix capable of minimizing the diffusion of water into the matrix.Suitable polymers comprising the matrix include poly(lactide) (PLA)polymers and the lactide/(glycolide) (PLGA) copolymers as describedearlier.

Alternatively, the sustained release delivery system may comprisepoly-anionic molecules or resins that are suitable for injection or oraldelivery. Suitable polyanionic molecules include cyclodextrins andpolysulfonates formulated to form a poorly soluble mass that minimizesexposure of the prodrug to water and from which the prodrug slowlyleaves. Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

In preferred embodiments, the compounds of the invention, orpharmaceutical compositions comprising one or more compounds of theinvention, are administered parenterally, for example, by intramuscular,subcutaneous or intraperitoneal injection. Without being bound bytheory, it is believed that upon injection, compounds of the inventionform an insoluble or sparingly soluble depot from which prodrugmolecules are released over time.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg.

Effective doses will also vary depending on route of administration, thepossibility of co-usage with other agents and the duration of release ofthe parent drug. It will be understood, however, that the total dailyusage of the compounds and compositions of the present invention will bedecided by the attending physician within the scope of sound medicaljudgment. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or contemporaneously with the specific compound employed;and like factors well known in the medical arts.

The compounds of this invention can be administered to a human or otheranimal in single or in divided doses, and can be in amounts for examplebetween 0.1 to about 2,000 mg. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily, weekly, biweekly,triweekly or monthly dose. In general, treatment regimens according tothe present invention comprise administration to a patient in need ofsuch treatment from about 5 mg to about 1000 mg of the compound(s) ofthis invention on a daily, weekly, biweekly, triweekly or monthly singlydose.

The compounds of the invention can, for example, be administered byinjection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation.

In a preferred embodiment, the administration of the compounds of theinvention results in sustained or controlled release. The compounds ofthe invention can be administered with a dosage ranging from about 0.1to about 2000 mg, Alternatively dosages can be between about 1 mg andabout 1000 mg/dose, or between about 5 and about 800 every day, everyweek, every two weeks, every three weeks or every month, or according tothe requirements of the particular drug. Lower or higher doses thanthose recited above may be required. Specific dosage and treatmentregimens for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health status, sex, diet, time ofadministration, rate of excretion, drug combination, the severity andcourse of the disease, condition or symptoms, the patient's dispositionto the disease, condition or symptoms, and the judgment of the treatingphysician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Preferred compounds of the invention exhibit sustained activityfollowing dosing compared to dosing with the parent drug. For example,when administered by the same route in the same amount (as measured byequivalents of parent drug), the compounds of the invention providesustained therapeutic serum levels of parent drug for a significantlylonger time than the parent drug. Such administration can be oral, withsustained delivery over hours, or parenteral, with sustained deliveryover days, weeks or months.

Representative compounds of the invention include the compounds setforth in Table 4 below.

TABLE 4 Compound # Structure 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g. single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, and substituted or unsubstituted cycloalkyl groupsas described herein.

The term “acyl” refers to a carbonyl substituted with hydrogen, alkyl,partially saturated or fully saturated cycloalkyl, partially saturatedor fully saturated heterocycle, aryl, or heteroaryl. For example, acylincludes groups such as (C₁-C₆) alkanoyl (e.g., formyl, acetyl,propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted, saturated aliphatic hydrocarbonradicals/groups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”) preferablyabout 7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about24 carbon atoms (“C₈-C₂₄”), preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkyl groups comprise at about 1 to about 8carbon atoms (“C₁-C₈”) such as about 1 to about 6 carbon atoms(“C₁-C₆”), or such as about 1 to about 3 carbon atoms (“C₁-C₃”).Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,neopentyl and n-hexyl radicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkenyl radicals are “lower alkenyl”radicals having two to about ten carbon atoms (“C₂-C₁₀”) such asethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Preferred loweralkenyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”). The terms“alkenyl”, and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkynyl” refers to linear or branched radicals having at leastone carbon-carbon triple bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkynyl radicals are “lower alkynyl”radicals having two to about ten carbon atoms such as propargyl,1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl. Preferredlower alkynyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”).

The term “cycloalkyl” refers to saturated carbocyclic radicals havingthree to about twelve carbon atoms (“C₃-C₁₂”). The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “cycloalkenyl” refers to partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight chain or branched saturated hydrocarbon chain having thespecified number of carbons atoms. Examples of alkylene groups include,but are not limited to, ethylene, propylene, butylene,3-methyl-pentylene, and 5-ethyl-hexylene.

The term “alkenylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbondouble bond. Alkenylene groups include, but are not limited to, forexample, ethenylene, 2-propenylene, 2-butenylene,1-methyl-2-buten-1-ylene, and the like.

The term “alkynylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbontriple bond. Representative alkynylene groups include, but are notlimited to, for example, propynylene, 1-butynylene,2-methyl-3-hexynylene, and the like.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” refers to alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a pentavalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” refers to heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radical.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty-four carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred alkylthio radicals have alkyl radicalswhich are “lower alkylthio” radicals having one to about ten carbonatoms. Most preferred are alkylthio radicals having lower alkyl radicalsof one to about eight carbon atoms. Examples of such lower alkylthioradicals include methylthio, ethylthio, propylthio, butylthio andhexylthio.

The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” refers to aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” refers to alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty-four carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred aminoalkyl radicals are “loweraminoalkyl” that have alkyl radicals having one to about ten carbonatoms. Most preferred are aminoalkyl radicals having lower alkylradicals having one to eight carbon atoms. Examples of such radicalsinclude aminomethyl, aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The terms “compound”, “drug”, and “prodrug” as used herein all includethe compounds, drugs and prodrugs having the formulas disclosed herein.The compounds of the invention can occur in forms includingpharmaceutically acceptable salts, solvates, hydrates, crystallineforms, amorphous forms, polymorphs, enantiomers, diastereoisomers,racemates and the like.

As used herein, the term “effective amount of the subject compounds,”with respect to the subject method of treatment, refers to an amount ofthe subject compound which, when delivered as part of desired doseregimen, brings about management of the disease or disorder toclinically acceptable standards.

“Treatment” or “treating” refers to an approach for obtaining beneficialor desired clinical results in a patient. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, one or more of the following: alleviation of symptoms,diminishment of extent of a disease, stabilization (i.e., not worsening)of a state of disease, preventing spread (i.e., metastasis) of disease,preventing occurrence or recurrence of disease, delay or slowing ofdisease progression, amelioration of the disease state, and remission(whether partial or total).

EXAMPLES

The compositions and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the processes,formulations and/or methods of the invention may be made withoutdeparting from the spirit of the invention and the scope of the appendedclaims.

Synthesis of Compounds

The compounds of the invention can be synthesized by the method setforth in Schemes 1A and 1B.

Schemes 1A and 1B illustrate the synthesis of a compound of Formula I bycondensation of the parent drug compound with chloromethylchloroformate, followed by condensation with a carboxylic acid.

Example 1 (tetradecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(Compound 127)

Synthesis of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A]:

To a solution of olanzapine (18.0 g, 57.7 mmol) and triethylamine (16mL, 0.12 mol) in dichloromethane (250 mL) was warmed to 35° C. and oncea clear solution formed, the reaction was cooled to 5 OC. To this wasadded chloromethyl chloroformate (7.6 mL, 86.5 mmol) over 20 minutes.The reaction was stirred at room temperature for 30 min and allowed towarm to room temperature. After 15 min at room temperature the reactionmixture was diluted with dichloromethane (100 mL), then washed with aqsatd NaHCO₃ (75 mL) and water (350 mL). The organic phase was dried overMgSO₄ and filtered. The organic phase was then concentrated under vacuumat 45° C. to a volume of ˜150 mL. The mixture was diluted with ethylacetate (30 mL) and ˜20-30 mL further was evaporated under vacuum. Themixture was cooled to room temperature and the resulting solidprecipitate filtered and washed with ethyl acetate. After drying undervacuum at 35° C. for 90 min chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A](17.1 g, 73%) was obtained as a yellow solid.

¹H-NMR (300 MHz, CDCl₃) δ 7.62-7.14 (4H, m), 6.27-6.22 (1H, m),5.84-5.69 (1H, m), 5.47-5.23 (1H, m), 3.89-3.63 (4H, m), 2.66-2.22 (10H,m).

General Procedure for the Synthesis of Aliphatic Carboxylic AcidSubstituted Compounds Derived from [A]:

To a solution of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[A] (1 equiv) in dimethylformamide ((13 mL/g of [A])) was added cesiumcarbonate (1 equiv) and the appropriate aliphatic carboxylic acid (2equiv). The reaction mixture was heated at 60 OC for 2-6 h, untilstarting material [A] had been consumed (loss of starting materialdetermined by TLC). The reaction mixture was cooled, diluted withsaturated aqueous NaHCO₃ (50 mL/g of [A]) and diethyl ether (75 mL/g of[A]). After being stirred for 15 min the mixture was filtered throughcelite and the organic phase separated. This was dried over MgSO₄ andevaporated. The residue was purified by column chromatography on silicaeluting with 30% THF in EtOAc and the product containing fractioncombined and evaporated. The residue was co-evaporated from hexanes.

Using the procedure as described above gave (tetradecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate,Compound 127 (1.95 g, 48%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.63-7.54 (1H, m), 7.46-7.37 (1H, m),7.36-7.26 (1H, m), 7.18-7.05 (1H, m), 6.28-6.19 (1H, m), 5.66-5.56(1.5H, m), 5.38-5.34 (1H, m), 3.90-3.80 (2H, m), 3.69-3.54 (2H, m),2.50-2.40 (4H, m), 2.32-2.25 (6H, m), 1.61-1.51 (2H, s), 1.32-1.22 (14H,m), 0.87 (3H, t). [M+H]⁺=597.06.

Example 2 (palmitoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(Compound 56)

Using the procedure as described above for (octanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylateexcept heated at 60° C. for 1 day gave (palmitoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylateCompound 56 (1.51 g, 75%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.62-7.55 (1H, m), 7.45-7.21 (2H, m),7.17-7.08 (1H, m), 6.26-6.20 (1H, m), 5.66-5.35 (2H, m), 3.90-3.79 (2H,m), 3.68-3.54 (2H, m), 2.47-2.45 (4H, m), 2.33-2.24 (8H, m), 1.61-1.50(2H, m), 1.35-1.15 (24H, m), 0.92-0.81 (3H, m).

Example 3 (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(Compound 111)

Using the procedure as described above for (octanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylategave (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylateCompound 111 (1.51 g, 75%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.63-7.54 (1H, m), 7.46-7.37 (1H, m),7.36-7.26 (1H, m), 7.18-7.07 (1H, m), 6.28-6.19 (1H, m), 5.67-5.56(1.5H, m), 5.38-5.34 (1H, m), 3.91-3.78 (2H, m), 3.69-3.54 (2H, m),2.50-2.40 (4H, m), 2.31-2.24 (6H, m), 1.61-1.50 (2H, s), 1.34-1.20 (30H,m), 0.87 (3H, t). [M+H]⁺=653.14.

Example 4 (icosanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(Compound 112)

Using the procedure as described above for (octanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylategave (icosanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylateCompound 112 (1.51 g, 75%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.63-7.54 (1H, m), 7.46-7.37 (1H, m),7.36-7.26 (1H, m), 7.18-7.07 (1H, m), 6.28-6.19 (1H, m), 5.67-5.57(1.5H, m), 5.37-5.34 (1H, m), 3.90-3.78 (2H, m), 3.69-3.53 (2H, m),2.49-2.40 (4H, m), 2.32-2.24 (6H, m), 1.61-1.50 (2H, s), 1.34-1.20 (34H,m), 0.87 (3H, t). [M+H]⁺=681.19.

Example 5 1-(palmitoyloxy)ethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(Compound 142)

Synthesis of chloroethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[B].

To a solution of olanzapine (1.70 g, 5.44 mmol) in dichloromethane (50mL) at 0° C. was added triethylamine (1.14 mL, 8.16 mmol) followed by1-chloroethyl chloroformate (0.70 mL, 6.53 mmol) dropwise. TLC after 3hours indicated starting material still remaining therefore more1-chloroethyl chloroformate (0.2 mL) was added and stirred for a further2 hours. The reaction was diluted with dichloromethane (20 mL) andwashed with aq satd NaHCO₃ (50 mL), dried (MgSO₄) and concentrated. Thecrude product was purified by column chromatography on silica elutingwith 2-5% MeOH/dichloromethane to give 1-chloroethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate(1.33 g, 58% yield) as an orange foam.

¹H-NMR (300 MHz, CDCl₃) δ 7.61-7.55 (1H, m), 7.45-7.09 (3H, m),6.41-6.21 (2H, m), 3.88-3.82 (2H, m), 3.67-3.58 (2H, m), 2.53-2.50 (4H,m), 2.32-2.29 (6H, m), 1.63-1.46 (3H, m).

General Procedure for the Synthesis of Aliphatic Carboxylic AcidSubstituted Compounds Derived from [B]:

The appropriate aliphatic carboxylic acid (1.5 equiv) anddiisopropylethylamine (1.5 equiv) were premixed then added to1-chloroethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate[B] (1 equiv). The reaction was cooled to room temperature, diluted withdiethyl ether (50 mL/g [B]), washed with aq satd NaHCO₃ (50 mL/g [B]),brine (50 mL/g [B]), dried (MgSO₄) and concentrated. The crude productwas purified by column chromatography on silica eluting with 1%triethylamine/dichloromethane then further purified using columnchromatography on silica eluting with 2-4% MeOH/dichloromethane.

Using the procedure as described above gave 1-(palmitoyloxy)ethyl2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate,Compound 142 (1.36 g, 54%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.60-7.54 (1H, m), 7.43-7.03 (3H, m),6.64-6.54 (1H, m), 6.26-6.21 (1H, m), 3.93-3.80 (2H, m), 3.76-3.55 (2H,m), 2.48-2.40 (4H, m), 2.33-2.20 (8H, m), 1.64-1.50 (2H, m), 1.35-1.16(27H, m), 0.92-0.83 (3H, m). [M+H]⁺=639.57.

Example 6 General Procedure for the Synthesis of Compounds-7-9

Synthesis of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate[C]

To a solution of olanzapine (5.0 g, 16 mmol) in tetrahydrofuran (50 mL)at −78° C. was added tetramethylethylenediamine (2.4 mL, 16 mmol),followed by 2M n-BuLi in hexanes (8.0 mL, 16 mmol) over 5 min. Thereaction mixture was stirred for 15 min and then chloromethylchloroformate (2.1 mL, 24 mmol) added and the reaction mixture stirred afurther 30 min. The reaction mixture was then warmed to roomtemperature, stirred for 1 h and quenched with water (50 mL). Thismixture was diluted with brine (50 mL) and extracted with ethyl acetate(50 mL). The organic phase was dried over MgSO₄, evaporated and theresidue further purified by column chromatography on silica eluting with0.2:1:1 methanol/dichloromethane/ethyl acetate to give chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate[C](5.6 g, ˜50% pure by ¹H NMR and LCMS). This was used directly in thenext reaction without further purification.

¹H-NMR (300 MHz, CDCl₃) δ 7.02-7.30 (4H, m), 6.45 (1H, s), 5.78-5.92(1.5H, m), 5.52-5.60 (0.5H, m), 3.50-3.70 (4H, m), 2.35-2.55 (7H, m),2.32 (3H, s). [M+H]⁺=405.0.

General Procedure for the Synthesis of Aliphatic Carboxylic AcidSubstituted Compounds Derived from [C]:

To a solution of chloromethyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(C:1 equiv) in dimethylformamide (13 mL/g of [C]) was added Cs₂CO₃ (1equiv) and the appropriate aliphatic carboxylic acid (2 equiv). Thereaction mixture was heated at 65° C. for 2-6 h, until starting material[A] had been consumed (loss of starting material determined by TLC). Thereaction mixture was cooled, diluted with saturated aqueous NaHCO₃ (50mL/g of [C]) and ethyl acetate (75 mL/g of [C]). After being stirred for15 min the mixture was filtered through celite and the organic phaseseparated. This was dried over MgSO₄ and evaporated. The residue wasfurther purified by column chromatography on silica eluting with 1:9methanol/ethyl acetate and after evaporation of the product containingfractions, the residue was co-evaporated with hexane (2×10 mL/g [C]).

Example 7 (tetradecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound 6)

Using the general procedure described in Example 6 above employingtetradecanoic acid and 2.8 g of the intermediate [A], provided(tetradecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound 7) (1.60 g, 39% yield) as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.00-7.25 (4H, m), 6.43 (1H, s), 5.62-5.90(2H, m), 3.51-3.65 (4H, m), 2.30-2.56 (10H, m), 1.58-1.66 (2H, m),1.20-1.34 (22H), 0.87 (3H, t). [M+H]+=597.12.

Example 8 (hexadecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound 7)

Using the general procedure described in Example 6 above employingpalmitic acid and 1.0 g of the intermediate [A], provided(hexadecanoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound 8) (1.60 g, 39% yield) as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 7.00-7.25 (4H, m), 6.43 (1H, s), 5.62-5.90(2H, m), 3.51-3.66 (4H, m), 2.30-2.56 (10H, m), 1.58-1.68 (2H, m),1.20-1.34 (26H), 0.87 (3H, t). [M+H]+=625.07.

Example 9 (stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound 8)

Using the general procedure described in Example 6 above employingstearic acid and 2.8 g of the intermediate [A], provided(stearoyloxy)methyl2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine-10-carboxylate(Compound-9) (1.44 g, 32% yield) as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ 6.99-7.22 (4H, m), 6.43 (1H, s), 5.62-5.88(2H, m), 3.51-3.66 (4H, m), 2.30-2.66 (10H, m), 1.55-1.70 (2H, m),1.20-1.34 (30H), 0.87 (3H, t). [M+H]⁺=653.21.

Example 10 Pharmacokinetic Evaluation of Prodrugs in Rats

Animals

Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass.)25 male Sprague-Dawley rats are obtained. Approximately 24 rats are usedin each study. Rats are approximately 325-350 g at time of arrival, andare housed 2 per cage with ad libitum chow and water. Environmentalconditions in the housing room are 64-76° F., 30% to 70% relativehumidity, and 12:12-h light:dark cycle. All experiments are approved bythe Institutional Animal Care and Use Committee.

Test Compounds Prodrug compounds (Compound 56, Compound 111, andCompound 112) of the invention and corresponding parent drugs of theprodrugs are tested.

Pharmacokinetics StudyAnimals

Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass.)25 male Sprague-Dawley rats are obtained. Approximately 24 rats are usedin each study. Rats are approximately 325-350 g at time of arrival, andare housed 2 per cage with ad libitum chow and water. Environmentalconditions in the housing room are 64-76° F., 30% to 70% relativehumidity, and 12:12-h light:dark cycle. All experiments are approved bythe Institutional Animal Care and Use Committee.

Test Compounds

Prodrug compounds (Compound 56, Compound 111 and Compound 112) of theinvention and corresponding parent drugs of the prodrugs are tested.

Pharmacokinetics Study

Rats are dosed IM by means of a 25 gauge, ⅝ in. needle with 1 ccsyringe. 0.3 mL suspension is withdrawn from the vial containing thetest compound. The rat is injected in the muscles of the hind limb afteranesthesia with isoflourane. Blood samples are collected via a lateraltail vein after brief anesthesia with Isoflurane. A 27½G needle and 1 ccsyringe without an anticoagulant is used for the blood collection.Approximately 250 μL of whole blood is collected at each sampling timepoint of 1 hour, 6 hours, 24 hours and 2, 3, 6, 7, 10, 14 days afteradministration. Once collected, whole blood is immediately transferredto tubes containing an esterase inhibitor and anti-coagulant, inverted10-15 times and immediately placed on ice. The tubes are centrifuged for2 minutes at >14,000 g's (11500 RPMs using Eppendorf Centrifuge at 2-6°C. to separate plasma. Plasma samples are transferred to labeled plaintubes and stored frozen at <−70° C. The study design is shown in Table 5and the PK results are given in Table 6.

TABLE 5 Active Dose # of Dose Conc. Volume Compound Vehicle GroupAnimals (mg) (mg/mL) (mL) Route Relprevv Zyprexa A 3 3 10 0.3 IMCompound CMC Vehicle C 6 3 10 0.3 IM 56 (2% CMC, 0.2% Tween 20 in 10 mMPBS pH 6.8,) Compound CMC Vehicle D 6 3 10 0.3 IM 111 (2% CMC, 0.2%Tween 20 in 10 mM PBS pH 6.8,) Compound CMC Vehicle E 6 3 10 0.3 IM 112(2% CMC, 0.2% Tween 20 in 10 mM PBS pH 6.8,)

TABLE 6 OLZ OLZ OLZ Relative OLZ AUC_(INF) T_(max) C_(max) T_(last) ^(x)exposure of Compound (hr * ng/mL) (hr) (ng/mL) (hr) prodrug^(y) Relprevv1535 6 63.2 168 — Compound 56 1791 48 16.6 >336 Not detected Compound111 2170 48 13.6 >336 <3% Compound 112 1293 148 6.0 >336 12% ^(t)Thisconcentration was extrapolated above the upper limit of quantification(100 ng/mL). ^(x)The last time point with a measured concentration abovethe lower limit of quantitation. ^(y)Calculated using the formula:([Prodrug AUC_(last)/(MW_(prodrug))]/[OLZ AUC_(INF)/(MW_(OLZ))]) * 100

CONCLUSIONS

Three of the compounds (56, 111, and 112) provided sustained releaseconcentrations of Olanzapine for at least 14 days, with delayed T_(max)and T_(last), and lower C_(max) relative to the current commercialextended release injectable, Relprevv (Olanzapine Pamoate salt). Theslow absorption of these compounds is illustrated by the delayedOlanzapine T_(max). All of the compounds efficiently deliver Olanzapine,providing exposures of Olanzapine that are comparable to the measuredOlanzapine exposure delivered by Relprevv. In addition, the relativeexposure of the prodrugs as compared on a molar basis to that ofOlanzapine is low in all cases.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims. It should also be understood thatthe embodiments described herein are not mutually exclusive and thatfeatures from the various embodiments may be combined in whole or inpart in accordance with the invention.

What is claimed is:
 1. A compound selected from:

wherein: R₁ is —C(O)OCH₂OC(O)R₆; and R₆ is selected from C₁₃-C₂₆-alkyl,substituted C₁₃-C₂₆-alkyl, C₁₃-C₂₆-alkenyl, substituted C₁₃-C₂₆-alkenyl,C₁₃-C₂₆-alkynyl, and substituted C₁₃-C₂₆-alkynyl.
 2. A compoundaccording to claim 1, wherein R₆ is selected from C₁₃-C₂₅-alkyl,substituted C₁₃-C₂₅-alkyl, C₁₃-C₂₅-alkenyl, substituted C₁₃-C₂₅-alkenyl,C₁₃-C₂₅-alkynyl, and substituted C₁₃-C₂₅-alkynyl.
 3. A compoundaccording to claim 1, wherein R₆ is selected from C₁₇-C₂₁-alkyl,substituted C₁₇-C₂₁-alkyl, C₁₇-C₂₁-alkenyl, substituted C₁₇-C₂₁-alkenyl,C₁₇-C₂₁-alkynyl, and substituted C₁₇-C₂₁-alkynyl.
 4. A compoundaccording to claim 1, wherein R₆ is selected from C₁₇-alkyl, substitutedC₁₇-alkyl, C₁₇-alkenyl, substituted-C₁₇ alkenyl, C₁₇-alkynyl, andsubstituted C₁₇-alkynyl.
 5. A compound according to claim 1, wherein R₆is selected from C₁₉-alkyl, substituted C₁₉-alkyl, C₁₉-alkenyl,substituted C₁₉-alkenyl, C₁₉-alkynyl, and substituted C₁₉-alkynyl.
 6. Acompound according to claim 1, wherein R₁ is selected from


7. A compound selected from Compound # Structure
 10.


11.


12.


13.


14.


28.


29.


30.


37.


38.


39.


43.


44.


45.


49.


50.


51.


62.


63.


64.


65.


66.


67.


68.


69.


70.


84.


85.


86.


93.


94.


95.


99.


100.


101.


105.


106.


107.


129.


130.


131.


132.


133.

134


8. An injectable depot formulation comprising a compound according toclaim
 1. 9. The injectable depot formulation of claim 8, wherein saidcompound is released over a period of at least one day.
 10. Theinjectable depot formulation of claim 8, wherein said compound isreleased over a period of at least one to two days.
 11. The injectabledepot formulation of claim 8, wherein said compound is released over aperiod of at least seven days.
 12. The injectable depot formulation ofclaim 8, wherein said compound is released over a period of more thanone week.
 13. The injectable depot formulation of claim 8, wherein saidcompound is released over a period of at least two weeks.
 14. Thecompound of claim 1, wherein R₆ is selected from C₁₅-C₂₃-alkyl,substituted C₁₅-C₂₃-alkyl, C₁₅-C₂₃-alkenyl, substituted C₁₅-C₂₃-alkenyl,C₁₅-C₂₃-alkynyl, and substituted C₁₅-C₂₃-alkynyl.
 15. A pharmaceuticalcomposition comprising a compound according to claim 1, and apharmaceutically acceptable carrier or excipient.